Given the importance of indole drugs, efficient, cost-effective, and high purity yielding synthetic and manufacturing processes are needed.
For example, bazedoxifene and pipendoxifene each belongs to the class of selective oestrogen receptor modulators (SERMs). SERMs are defined as substances that bind to the oestrogen (also known as estrogen) receptor with high affinity and at the same time have do not show significant binding activity with other nuclear receptors. In contrast to oestrogens, however, they lead in the various target tissues to “oestrogen-agonistic” or “oestrogen-antagonistic” action. Bazedoxifene is effective in the prevention and treatment of osteoporosis and in particular of postmenopausal osteoporosis.
Several synthetic processes have been reported for bazedoxifene (see, for example, U.S. Pat. Nos. 5,998,402, 7,683,051, 7,683,052, and 8,034,807, US application publication Nos. 2010/0016290, 2010/0016581, and 2010/0016582, EP published application No. 1777214, and PCT international application publication Nos. WO 99/019293, WO 2011/022596, and WO 2012/007453). However, current and conventional processes have been reported to be expensive due to a number of factors, including the cost of reagents, the necessary isolation and purification of intermediates by chromatography, and yield losses due to unwanted side reactions, including C-alkylation during formation of the N−1 substituted indoles.
It has been discovered that the processes described herein for preparing indole drugs, such as but not limited to bazedoxifene, pipendoxifene, and the like, provide the desired compound with high efficiency, low cost, and with fewer accompanying side products than conventional processes. In addition, it has been discovered that the processes described herein for preparing indole drugs, such as but not limited to bazedoxifene, pipendoxifene, and the like, provide several crystalline intermediates that improve overall purity and in high yield.
In one illustrative embodiment of the invention, processes for preparing compounds of the following formula are described herein:
and pharmaceutically acceptable salts thereof, wherein
Ar1, Ar2, and Ar3 are each independently selected aryl, each of which is optionally substituted;
RA is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl;
RB is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and
R2 is hydrogen, or represents one or more aryl substituents, including but not limited to hydroxy and derivatives thereof.
In another illustrative embodiment, the processes described herein include one or more of the following steps:
(a) contacting a first compound of the formula
with a second compound of the formulaAr2—NHNH2 or a salt thereof; and/or
(b) contacting a first compound of the formula
or a salt thereof, with a reagent capable of converting the hydroxyl group into a leaving group to form a second compound of the formula
or a salt thereof, where L is the leaving group; and/or
(c) contacting a first compound of the formula
with a second compound of the formula
or a salt thereof, and a base; and/or
(d) contacting a compound of the formula
with an acid.
In another illustrative embodiment, the processes described herein are used to prepare compounds of the foregoing formulae, where one or more of Ar1, Ar2, and/or Ar3 is an independently selected protected phenol. In another embodiment, the processes described herein include the step of (e) contacting the protected phenol with a phenol deprotecting agent. In another embodiment, the processes described herein include the step of (f) crystallizing the deprotected phenol in the presence of an acid, or a carboxylic acid, or acetic acid to form the corresponding acid addition salt thereof.
In another embodiment, intermediate compounds useful for preparing the compounds of the foregoing formulae are described herein, including compounds of the formulae
and salts thereof, such as the HBr salt thereof; where n is 2, 3, 4, or 5; and each RN is independently selected from hydrogen and alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted, or both RN and the attached nitrogen are taken together to form a heterocyclyl radical.
In another embodiment, intermediate compounds useful for preparing the compounds of the foregoing formulae are described herein, including compounds of the formulae
and salts thereof, such as the HBr salt thereof; wherein n is 2, 3, 4, or 5; and m is 1, 2, 3, 4, 5, 6, or 7; and various subgenera and species thereof.
In another embodiment, intermediate compounds useful for preparing the compounds of the foregoing formulae are described herein, including compounds of the formulae
and salts thereof, such as the HBr salt thereof; wherein n is 2, 3, 4, or 5; and m is 1, 2, 3, 5, 6, or 7; and various subgenera and species thereof.
It is appreciated herein that the foregoing benzyl bromide intermediates may be advantageously isolated and used in the processes descried herein as the corresponding salts, such as the HBr salts, instead of the neutral amino compounds.
In another embodiment, intermediate compounds useful for preparing the compounds of the foregoing formulae are described herein, including compounds of the formulae
and salts thereof, wherein Ar1 and Ar2 are each independently selected aryl, each of which is optionally substituted; and RA is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and various subgenera and species thereof.
In another embodiment, intermediate compounds useful for preparing the compounds of the foregoing formulae are described herein, including compounds of the formulae
and salts thereof, wherein Ar1, Ar2, and Ar3 are each independently selected aryl, each of which is optionally substituted; RA is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and RB is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and various subgenera and species thereof.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with a disease responsive to a selective estrogen receptor modulator (SERM). It is to be understood that the compositions may include other component and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, the compounds and pharmaceutical compositions for treating patients with a disease responsive to a SERM are also described herein as being included in methods for using or treating, uses, and uses in the manufacture of medicaments.